Establishment of diagnosis method and analysis of genetic background of adult leukoencephalopathy patients with desktop next-generation sequencer

• Project/Area Number: 25461287
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Yokohama City University
• Principal Investigator: Ueda Naohisa 横浜市立大学, 大学病院, 准教授 (00305442)
• Co-Investigator(Kenkyū-buntansha): DOI Hiroshi 横浜市立大学, 医学部神経内科, 准教授 (10326035) ; TANAKA Fumiaki 横浜市立大学, 医学研究科神経内科, 教授 (30378012)
• Co-Investigator(Renkei-kenkyūsha): MATSUMOTO Naomichi 横浜市立大学, 医学研究科遺伝学, 教授 (80325638)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2014: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2013: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 次世代シーケンサー / カスタムキャプチャー / 白質脳症 / ターゲットキャプチャー

Outline of Final Research Achievements

Leukoencephalopathies comprise all clinical syndromes predominantly affecting the white matter of the brain. We performed capture-based target enrichment followed by next-generation sequencing for the genetic screening of adult leukoencephalopathy patients with unknown causes. We picked up 55 leukoencephalopathy-related genes and designed the bait library with SureSelect technology (Agilent). Genomic DNAs from 60 Japanese adult leukoencephalopathy patients were processed by this library, and the captured DNAs were analyzed by next generation sequencer MiSeq. As results, we detected pathological NOTCH3 mutations in 4 patients, and EIF2B2 and POLR3A mutations in one patient, respectively. Additionally, unreported mutations were detected in some patients. In our study, 10% of adult patients with leukoencephalopathy were definitively diagnosed with known or apparently pathological mutations, and 8.3% of patients had mutations with unconfirmed significance.

Research Products

• [Journal Article] A novel mutation in ELOVL4 leading to spinocerebellar ataxia (SCA) with the hot cross bun sign but lacking erythrokeratodermia: a broadened spectrum of SCA34. (2015)
  • Author(s): Ozaki K, Doi H, Mitsui J, Sato N, Iikuni Y, Majima T, Yamane K, Irioka T, Ishiura H, Doi K, Morishita S, Higashi M, Sekiguchi T, Koyama K, Ueda N, Miura Y, Miyatake S, Matsumoto N, Yokota T, Tanaka F, Tsuji S, Mizusawa H, Ishikawa K.
  • Journal Title: JAMA Neurology Volume: 72 Issue: 7 Pages: 797-805
  • DOI: 10.1001/jamaneurol.2015.0610
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A Japanese case of cerebellar ataxia, spastic paraparesis and deep sensory impairment associated with a novel homozygous TTC19 mutation (2015)
  • Author(s): Kunii M, Doi H, Higashiyama Y, Kugimoto C, Ueda N, Hirata J, Tomita-Katsumoto A, Kashikura-Kojima M, Kubota S, Taniguchi M, Murayama K, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Matsumoto N, Tanaka F.
  • Journal Title: J Hum Genet Volume: 60 Issue: 4 Pages: 187-191
  • DOI: 10.1038/jhg.2015.7
  • NAID: 40020433141
  • Peer Reviewed / Open Access
• [Journal Article] Late-onset spastic ataxia phenotype in a patient with a homozygous DDHD2 mutation (2014)
  • Author(s): Doi H, Ushiyama M, Baba T, Tani K, Shiina M, Ogata K, Miyatake S, Yuzawa YF, Tsuji S, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Ikeda S, Tanaka F, Matsumoto N, Yoshida K
  • Journal Title: Sci Rep Volume: 4 Issue: 1 Pages: 7132-7132
  • DOI: 10.1038/srep07132
  • NAID: 120007100602
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative analysis of upper-limb ataxia in patients with spinocerebellar degeneration (2014)
  • Author(s): Naohisa Ueda, Yasuhito Hakii, Shigeru Koyano, Yuichi Higashiyama, Hideto Joki, Yasuhisa Baba, Yume Suzuki, Yoshiyuki Kuroiwa, Fumiaki Tanaka
  • Journal Title: Journal of Neurology Volume: 印刷中 Issue: 7 Pages: 1381-1386
  • DOI: 10.1007/s00415-014-7353-4
  • Peer Reviewed
• [Journal Article] Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses. (2014)
  • Author(s): Ishiura H, Takahashi Y, Hayashi T, Saito K, Furuya H, Watanabe M, Murata M, Suzuki M, Sugiura A, Sawai S, Shibuya K, Ueda N, Ichikawa Y, Kanazawa I, Goto J and Tsuji S
  • Journal Title: J Hum Genet Volume: 59 Issue: 3 Pages: 163-172
  • DOI: 10.1038/jhg.2013.139
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] HIV感染症のART療法中に感染源不明の白質脳症を伴う免疫再構築症候群をきたした1例 (2015)
  • Author(s): 三宅綾子ら
  • Organizer: 第33回日本神経治療学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-11-26
• [Presentation] 脊髄小脳変性症における運動学習障害の評価 (2015)
  • Author(s): 上田直久ら
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-20
• [Presentation] 脊髄小脳変性症における運動学習障害の評価 (2014)
  • Author(s): 上田直久ら
  • Organizer: 第33回 日本認知症学会学術集会
  • Place of Presentation: パシフィコ横浜会議センター（横浜市西区）
  • Year and Date: 2014-11-29 – 2014-12-01
• [Presentation] Lewy小体型認知症，および認知症を伴うParkinson病にお けるMRI上の大脳白質病変の検討. (2014)
  • Author(s): 上木英人ら
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場（福岡市博多区）
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] 脊髄小脳変性症における運動学習障害の評価 (2014)
  • Author(s): 上田直久ら
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場（福岡市博多区）
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] 渦巻き描記を用いた小脳性運動失調の他覚的評価法の検討（第7報）
  • Author(s): 上田直久，波木井靖人，黒岩義之，田中章景
  • Organizer: 第54回日本神経学会総会
  • Place of Presentation: 国際フォーラム（東京）